The role of troponin and albumin to assess myocardial dysfunction after cardiac surgery and
in the critically ill
van Beek, Dianne E.C.
DOI:
10.33612/diss.101333600
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van Beek, D. E. C. (2019). The role of troponin and albumin to assess myocardial dysfunction after cardiac
surgery and in the critically ill. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.101333600
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Chapter
Dianne van Beek, Marc Königs, Yvette Kuijpers, Iwan van der Horst, Thomas Scheeren. Journal of Critical Care
Predictive value
of serum albumin levels
on noradrenaline and fluid
requirements in the first 24
hours after admission to
the Intensive Care Unit –
a prospective observational study
Abstract
Background: To determine the predictive value of serum albumin (SA) at admission to the intensive care unit (ICU) on the cumulative dose of noradrenaline, the fluids administered, the lactate level, and mortality during the first 24 hours of ICU admission.
Methods: A total of 100 ICU patients were included. The association between SA and the cumulative dose of noradrenaline was analyzed using logistic regression. For the total amount of fluids administered linear regression, for the lactate level and for 24-hours mortality logistic regression was used. Age, gender, patient category, type of surgery, severe sepsis, lactate level, estimated glomerular filtration rate, c-reactive protein level, and the target mean arterial pressure were considered effect modifiers.
Results: SA was significantly associated with the dose of noradrenaline (OR 0.92, 95% CI 0.84-0.99, p=0.028), lower lactate levels (OR 1.14, 95% CI 1.00-1.30, p=0.049), and with the amount of fluids administered (B -0.02, 95% CI -0.03/-0.00, p 0.016), but not with mortality (OR 0.95, 95% CI 0.85-1.07, p = 0.41)
Conclusions: SA significantly predicts noradrenaline dosing, the amount of fluids administered and the change in lactate level during the first 24 hours of ICU admission. Our observations have to be validated in another large cohort.
6
Introduction
Serum albumin (SA) is an independent predictor for mortality.1 The predictive value of SA at admission has been shown for mortality in patients admitted to an intensive care unit (ICU) patients.2;3 Although trials with albumin supplementation in ICU patients showed inconsistent results on mortality4 it is noteworthy that albumin supplementation resulted in a less positive fluid balance5,6 and an improved organ function measured by the Sequential Organ Failure Assessment (SOFA) score6. These studies, however, evaluated these outcomes during a prolonged ICU stay. In addition, these studies evaluated the effect of albumin supplementation and not the SA level itself on these outcomes. SA has been known as an negative acute phase protein in acute illness.7 The decrease in SA in acute illness is due to an increased vascular permeability, which results in a rate of loss of SA to tissues that greatly exceeds the rate of synthesis.8 During major abdominal surgery about 40% of SA is lost from the circulation, possibly due to capillary leakage and overhydration.9 Two days after major abdominal surgery SA is still decreased by 33% from before surgery, while the plasma volume and the absolute synthesis rate of SA were not significantly different from baseline.10
It is unclear whether SA is merely a marker of severity of disease or part of a causal pathway. The importance of SA to maintain blood oncotic pressure and its positive effect on the integrity of vascular walls supports the hypothesis that SA is important in maintaining intravascular volume7;11. Maintenance of an adequate intravascular volume could potentially reduce the need for vasopressors (e.g. noradrenaline) or inotropes and fluid support in ICU patients. Dose of noradrenaline in ICU patients with sepsis was shown to be an independent risk factor for mortality.12 Another recent study showed that the cumulative dose of vasopressors during the first 24 hours of ICU admission in patients with sepsis was significantly associated with early mortality.13
If indeed albumin could reduce the need for vasopressors, inotropes and/or fluid support, one would expect that the SA at admission is already associated with important ICU outcomes during the first 24 hours of ICU admission. Since ICU care is scarce it is important to be able to predict who will require and benefit the most from ICU admission.14 The objective of this study was to determine whether SA at admission to the ICU can be used to predict noradrenaline dosing and total amount of fluids administered during the first 24 hours of ICU admission. We also studied whether SA levels at admission are predictive for the arterial lactate level and mortality after 24 hours.
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Methods
This prospective observational cohort study took place in a 13-bed mixed medical and surgical intensive care unit (ICU) in the Maxima Medical Centre (MMC), the Netherlands. Data during the first 24 hours of ICU admission was collected from the electronic patient record system.
From January 2016 SA plasma level measurement became part of routine admission care on this ICU for patients who were expected to stay >24 hours in the ICU. From January through May 2016 a total of 100 consecutive patients in which SA was measured upon ICU admission were included in the study. During the study period, 192 patients were admitted to the ICU and in 100 patients SA was measured. To ensure the observational character of the study as much as possible and to ensure our research did not influence clinical practice, we did not conduct any analysis until after completion of the observational period. The MMC works with an opt-out system in which patients can object against using their anonymized medical data obtained for standard care for research purposes, none of the patients included in this study had objections. Because of the observational character of this study institutional review board (IRB) approval was not required.
The first measured SA level upon ICU admission was used for analysis. The maximum accepted time point for SA level upon admission was 3 hours after ICU admission. SA analysis was conducted using a calibrated colorimetric endpoint assay analyzer from Roche diagnostics with a reference range of 35-50 g/l. Arterial lactate level was measured in the laboratory of the hospital using Roche diagnostics blood gas analyzer with a reference range of 0.5-2.2 mmol/l. Severe sepsis was defined as sepsis with organ dysfunction (e.g. lactic acidosis, systolic blood pressure <90 mmHg)
For all other patients (with a BMI 18-27 kg/m2) no correction of the weight took place. However, for patients who were overweight (defined as a body mass index [BMI] > 27 kg/ m2) and for patients who were underweight (defined as a BMI < 18 kg/m2) the weight was corrected as follows: for the overweight patients (BMI >27 kg/m2) the weight that correlated with a BMI of 27 kg/m2 was calculated and used as the corrected weight throughout the analysis. For underweight patients, the weight that correlated with a BMI of 18 kg/m2 was calculated and used as the corrected weight throughout the analysis.
For the primary outcome, the cumulative dose of noradrenaline administered during the first 24 hours of ICU admission was calculated and given in micrograms (mcg) per corrected kilogram (mcg/corrected kg) of bodyweight. For the secondary outcome, the total amount of fluids administered during the first 24 hours of ICU admission was
6
calculated in milliliters (ml) per corrected kilogram of bodyweight. This was a combined total of all infused fluids (e.g. colloids, crystalloids and blood product transfusions) and all enteral fluids administered.
For every patient admitted to the ICU a target mean arterial pressure (MAP) in mmHg is ordered by the intensive care specialist. This target MAP is used to direct fluid and noradrenaline support. Usually, the target MAP is set at ≥65 mmHg and is adjusted per patient depending on their normal blood pressure and based on clinical variables (e.g. urinary output, neurologic status). To achieve this minimal MAP, the first choice would be to administer fluids (Ringers lactate) until the point the patient is no longer fluid responsive or until there are contraindications for administering fluids (e.g. severe pulmonary edema, cardiac failure). If the goal MAP cannot be achieved with administering fluids, noradrenaline is started and constantly adjusted to the minimal dose required to achieve the desired MAP.15 The highest ordered target MAP during the first 24 hours of ICU admission was collected for this study.
We selected a mean difference of SA of 5.0 g/l as our lowest clinical relevant difference to detect. This resulted in a sample size of 100 patients. As this sample size allowed to detect a difference of the mean SA of 5.0 g/l with a power of 0.85 and a type I error probability of 0.05, assuming the standard deviation (SD) of SA within each group is 6.0 g/l.
Statistical analysis
Baseline characteristics for different SA levels were presented as proportions, a mean with standard deviation (SD) or a median with interquartile ranges (IQR) where appropriate. The relationship between SA at ICU admission and noradrenaline requirement (yes or no) was first assessed using the independent sample student T test univariably and using the area under the curve of the receiver operator curve (AUC ROC). Subsequently, multivariable using log binominal regression was used to correct for potential effect modifiers. The primary outcome, the cumulative noradrenaline dose during the first 24 hours in mcg/ corrected kg was classified into four categories; no noradrenaline use (0 mcg/corrected kg), low dose of noradrenaline (0-100 mcg/ corrected kg), medium dose of noradrenaline (100-400 mcg/ corrected kg) and a high dose of noradrenaline (>400 mcg/corrected kg). The association between SA levels and noradrenaline category was analyzed using ordinal logistic regression.
The total amount of fluids administered was log transformed before analysis because of non-normality. The association between the secondary outcome, total amount of fluids administered during the first 24 hours of ICU stay and SA were analyzed as continuous
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variables using (multiple) linear regression. The lactate level after 24 hours was addressed as a multinominal variable (categories: not measured/ decreased compared to lactate level at admission/ increased compared to lactate level at admission) and analyzed using mulitnominal logistic regression. The association between the secondary outcome mortality during the first 24 hours of ICU stay and SA was analyzed using log binominal regression.
Potential effect modifiers were selected upon clinical knowledge. Patient related, treatment related and laboratory values were included in multivariate analysis; i.e. age, gender, category of patient: medical / abdominal surgery/ vascular surgery/ other surgery, type of surgery: no surgery/ elective surgery/ emergency surgery, severe sepsis, arterial lactate level at ICU admission, c- reactive protein (CRP) level at ICU admission, and estimated glomerular filtration rate (eGFR) <60ml/min (as estimated form the serum creatinine level using the CKD-EPI equation [chronic kidney disease epidemiology equation]), ordered minimal mean arterial pressure (MAP).
There were three potential effect modifiers with missing data: arterial lactate level upon ICU admission, CRP upon ICU admission, and ordered minimal MAP. Since it is unlikely that these data were missing completely at random, we addressed for this by changing these variables to multinominal variables. The minimal ordered MAP was categorized as: not available / low (<65 mmHg) / normal (65 mmHg) / high (>65 mmHg). The arterial lactate level upon ICU admission was categorized as: not available / normal (≤2.2 mmol/l) / elevated (> 2.2mmol/l). The CRP upon ICU admission was categorized as: not available/ normal (<10 mg/l)/ elevated (10-100mg/l)/ highly elevated (>100mg/l). All analyses were complete case analysis and an p<0.05 was considered significant.
Results
The median SA was 31 g/l (range 12 g/l to 47 g/l), and 49 (49%) of the patients had a mild to severe hypoalbuminemia upon ICU admission (table 1).
Primary outcome: noradrenaline requirement
The OR (odds ratio) for requiring noradrenaline (yes/no) decreased for every gram per liter increase of SA (OR 0.89, 95%CI 0.82-0.98, p=0.012). The AUC ROC was 0.682 (95% CI 0.576-0.785, p 0.002), a cut of value of 31.5 g/l resulted in a sensitivity of 67% and a specificity of 63% for requiring noradrenaline (figure 1).
6
Table 1. Baseline characteristics. Serum albumin - Severe hypoalbuminemia (</=25 g/l) - Mild hypoalbuminemia (26-35 g/l) - Normal albumin (>35 g/l) 25 (25%) 24 (24%) 51 (51%) Male gender 54 (54%)
Age in years 68 (IQR 51-80)
BMI (kg/m2) 25 (IQR 22-33) Severe sepsis 25 (25%) Surgical patient - Abdominal surgery - Vascular surgery - Pulmonary surgery - Gynecology surgery 23 (23%) 4 (4%) 2 (2%) 2 (2%) Urgent surgery 23 (23%)
Lactate at admission (mmol/l) 1.8 (IQR 1.1-4.5)
Lactate after 24 hours (mmol/l) 1.9 (IQR 0.8-6.3)
CRP (mg/l) 85 (IQR 10-296)
eGFR <60 ml/min 53 (53%)
Severe sepsis 25 (25%)
Goal MAP 65 (IQR 65-75)
Fluids administered within <24 hours (ml/corrected kg) 56 (SD 29)
Mechanical ventilation within < 24 hours 56 (56%)
CRP: c-reactive protein, eGFR: estimated glomerular filtration rate, BMI: body mass index, MAP: mean arterial pressure. Values are given as number (percentage) unless otherwise indicated
The OR for the categorized cumulative noradrenaline dose per kilogram during the first 24 hours also decreased for every gram per liter increase of SA in both unadjusted ordinal logistic regression (OR 0.92, 95%CI 0.87-0.97, p=0.003) and after correction for effect modifiers (OR 0.92, 95% CI 0.84-0.99, p=0.028) (table 2).
Secondary outcomes Fluids requirements
There was a significant negative linear relationship between the SA at admission and the log transformed amount of fluids administered per kilogram during the first 24 hours (B -0.04 [95% CI -0.03/-0.01], p 0.004, R2 0.08). After correction for effect modifiers, this negative linear relationship remained significant (B -0.02 [95% CI -0.03/-0.00], p 0.016, R2 0.37) (table 3).
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Figure 1.The area under the curve of the receiver operator curve (AUC ROC) for serum album (SA) to predict
noradrenaline requirements.
Table 2. Ordinal logistic regression results for serum albumin and categorized noradrenaline need during the
first 24 hours.
Factor Wald X2 OR (95% CI) P value
Unadjusted
albumin 8.95 0.92 (0.87-0.97) 0.003
Adjusted*
albumin 4.84 0.92 (0.84-0.99) 0.028
OR: odds ratio, CI: confidence interval. * Corrected for: age, gender, category of patient, type of surgery, severe sepsis, arterial lactate level upon admission, CRP level upon admission, glomerular filtration rate <60ml/min, goal minimal mean arterial pressure [MAP]
Table 3. Linear regression results for serum albumin and log transformed milliliters per kilogram fluid
administered during the first 24 hours.
factor B 95% CI P value R2
Univariable
albumin -0.04 -0.03/-0.01 0.004 0.08
Corrected for potential effect modifiers*
albumin -0.02 -0.03/-0.00 0.016 0.37
* Corrected for: age, gender, category of patient, type of surgery, severe sepsis, arterial lactate level upon admission, CRP level upon admission, glomerular filtration rate <60ml/min, goal minimal mean arterial pressure [MAP]
6
level after 24 hours
SA at ICU admission is significantly associated with the change in lactate level from admission to 24 hours after admission (p 0.022, R2 0.09) (figure 2). The OR for having
a decreased instead of increased lactate level after 24 hours increased for every gram per liter increase of SA (OR 1.16, 95% CI 1.02-1.32, p 0.021). After correction for effect modifiers this association remained significant (OR 1.14, 95% CI 1.00-1.30, p = 0.049).
Figure 2. The mean SA with the 95% CI for patients in who lactate was not measured, patients with an increased
and patients with a decreased serum lactate after 24 hours compared to serum lactate at admission
Mortality during the first 24 hours of ICU admission
The six patients who died during the first 24 hours of ICU admission had a mean SA of 28.3 ±3 g/l upon admission compared to a mean SA of 30.8 ±7 g/l of the patients who survived the first 24 hours. No association between SA at admission and mortality within 24 hours (OR 0.95, 95% CI 0.85-1.07, p = 0.41) was observed. The number of deaths within 24 hours were too small to draw any conclusions. Assuming that a difference in mean SA upon admission of 2.5 g/l between patients dying within 24 hours of ICU admission and those surviving is present, 594 patients are needed ( power of 80%, alpha of 0.05).
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Discussion
We found that SA levels upon ICU admission were significantly associated with requiring noradrenaline and the cumulative noradrenaline dose during the first 24 hours of ICU admission, an association that remained after extensive correction for potential effect modifiers. In addition, SA upon ICU admission was significantly linearly associated with the amounts of fluids administered per kilogram during the first 24 hours and with the odds for having a decreased lactate level after 24 hours, but not with short-term mortality. Our results are in line with a randomized controlled trial (n=1818) on albumin replacement in ICU patients with sepsis.5 In this trial a significant shorter duration of the need for inotropic support and a lower net fluid balance in the albumin replacement group was observed.5 Although our study did not investigate the effects of albumin infusion, we did show that the SA level itself is associated with these outcomes during the first 24 hours of ICU admission. The SAFE trial (n=6997) found that albumin infusion in the ICU compared to saline infusion resulted in less fluids administered during the first four days in a 1: 1.4 ratio.16
Our study was too small to show differences in SA levels and 24-hours mortality. The SAFE study group found that a SA < 25g/l was independently associated with 28-day mortality in ICU patients.18 They could not find a significant reduction in mortality when comparing albumin resuscitation with saline resuscitation regardless of the SA at admission.19 However, the mean SA of the group of patients receiving albumin transfusion was <25 g/L after 7 days.18 The non-significant association with mortality could be explained by a lack of power. Another explanation could be that the benefit of albumin administration on mortality is lower than expected, increasing the need for other relevant outcomes.20 One large (non ICU specific) meta-analysis stated that albumin transfusion significantly reduces morbidity.21
Noradrenaline requirement has been shown to be associated with mortality.7; 12 We found that a cut of value of 31.5 g/L resulted in a sensitivity of 67% and a specificity of 63% to predict noradrenaline requirement and that every g/l increase of SA significantly decreased the cumulative noradrenaline dose during the first 24 hours. Considering this a first step, future studies could be to establish whether albumin transfusion decreases the need for noradrenaline. A RCT with septic ICU patients already demonstrated that when SA was maintained above 30 g/l the duration of inotropic support needed was significantly shorter.22 SA is also considered the most important protein for determining blood oncotic pressure7, and the most important determinant of the interstitial oncotic pressure23 and the gradient between these two is likely important for fluid shifts.23 We hypothesize that
6
patient with a low SA have a decreased oncotic pressure and are less able to maintain fluids intravascular and thus are more prone to edema, limiting the maximum amount of fluids that can be administered. The association with edema might also relate to the positive effect of SA on the integrity of vascular walls7;11;24, although one study could not demonstrate a decrease in capillary membrane permeability after albumin administration in sepsis.23 We think that patients with a low albumin (and therefore a low oncotic pressure and vascular leakage), will require more noradrenaline. The interplay between SA and noradrenaline has been studied earlier and beside our hypotheses of a lower albumin is associated with higher requirements of noradrenaline and fluids, factors such as binding of catecholamines will interact25,26. This binding increases in the acute phase after surgery.27 Another possible mechanism for the reduction in noradrenaline requirement with increasing SA concentrations comes from animal studies: albumin infusion increases the contractility of the heart in rodents with cirrhosis and ascites possibly by a combined negative effect on iNOS expression and on the β-receptor-inhibitory G proteins.28 Reducing noradrenaline requirement is important, since noradrenaline requirement has been shown to be associated with mortality7;12 and noradrenaline damages erythrocytes11. In low cardiac output states lactate is formed in response to increased NaK-ATPase activity.29 Arterial lactate level after 24 hours of ICU admission has been shown to be a predictor for 28-day.30 Lactate level within 24 hours of ICU admission is also an independent predictor of in hospital mortality31 and in sepsis a reduction in lactate during the first 24 hours of ICU admission is associated with an improved outcome.32 Lactate is often measured at ICU admission and used to direct resuscitation as using lactate reduces mortality.33 In the surviving sepsis guideline it is recommended to continue resuscitation until lactate levels have normalized.34 We did find a significant association between SA at admission the odds for having a lower lactate level after 24 hours compared to the lactate level at admission. This study has several limitations; first, the number of patients were too small for strong conclusions. We suggest validating our observations in other cohorts. Second, there was a limited number of outcome data. The arterial lactate level after 24 hours was only measured in 36 patients and only 6 patients died within 24 hours. This resulted in underpowered analysis for these secondary outcomes. Third, as mentioned in the method section, there were missing data for two potential effect modifiers: arterial lactate level upon ICU admission and ordered minimal MAP. However, by changing these variables into multinominal variables we could include all patients in the analyses and correct for potential bias created by these missing variables. Fourth, we could not correct for BMI although this is a potential effect modifier, because we calculated our outcome per kilogram corrected body weight. In addition, we did not correct for a severity of disease score for similar reasons. The APACHE score includes SA and the SOFA score includes noradrenaline use,
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by correcting for these factors we would interfere with our analysis. However, both these scores are designed to predict the ICU mortality and not noradrenaline requirement and are thus not necessarily the most optimal effect modifiers for noradrenaline requirement. Finally, as mentioned in the method section, SA was not measured in every patient upon ICU admission. Most patients with no SA measurement were those with an expected stay in the ICU of <24 hours (e.g. intoxications). This means that there is a population bias of patients who were sicker at ICU admission and decreased the generalizability of the results. This potentially also explains why the mean SA at admission was below normal (30.7 g/l). Although it is likely that sicker patients, patients with a lower SA have more chance of requiring noradrenaline, we demonstrated that in this population of ‘sick’ ICU patients a significant ordinal relationship between SA and noradrenaline exists. Indicating that for every gram per liter increase in SA, the odds for needing a high dose of noradrenaline in mcg/kg decreased. In addition, some SA measurements were missing in patients with an expected stay of >24 hours. We believe that this data was missing at random and depends on the physician admitting the patient and the fact that SA measurements became part of routine care only very briefly before start of the study.
Conclusions
SA upon ICU admission was associated with important markers of the first 24 hours of ICU admission; namely the need for noradrenaline, the amounts of fluids administered and the change of lactate. This indicates that SA might be useful for identifying the sickest patients during the first 24 hours of ICU admission. The results of this study need to be validated in different ICU cohorts.
6
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